Combined analysis of copy number alterations by single-nucleotide polymorphism array and MYC status in non-metastatic breast cancer patients: comparison according to the circulating tumor cell status.

Recent technological advances have made it possible to detect circulating tumor cells (CTCs) as a prognostic marker in operable breast cancer patients. Whether the presence of CTCs in cancer patients correlates with molecular alterations in the primary tumor has not been widely explored. We identified 14 primary breast cancer specimens with known CTC status, in order to evaluate the presence of differential genetic aberrations by using SNP array assay. There was a global increase of altered genome, CNA, and copy-neutral loss of heterozygosity (cn-LOH) observed in the CTC-positive (CTC(+)) versus CTC-negative (CTC(-)) cases. As the preliminary results showed a higher proportion of copy number alteration (CNA) at 8q24 (MYC loci) and the available evidence supporting the role of MYC in the processes cancer metastases is conflicting, MYC status was determined in tissue microarray sections in a larger series of patients (n = 49) with known CTC status using FISH. MYC was altered in 62% (16/26) CTC(+) patients and in 43% (6/14) CTC(-) patients (p = 0.25). Based on the observation in our study, future studies involving a larger number of patients should be performed in order to definitively define if this correlation exists.

Prospective transGEICAM study of the impact of the 21-gene Recurrence Score assay and traditional clinicopathological factors on adjuvant clinical decision making in women with estrogen receptor-positive (ER+) node-negative breast cancer.

BACKGROUND: This study examined the impact of the Recurrence Score (RS) in Spanish breast cancer patients and explored the associations between clinicopathological markers and likelihood of change in treatment recommendations. PATIENTS AND METHODS: Enrollment was offered consecutively to eligible women with estrogen receptor-positive; human epidermal growth factor receptor 2-negative, node-negative breast cancer. Oncologists recorded treatment recommendation and confidence in it before and after knowing the patient's RS. RESULTS: Treatment recommendation changed in 32% of 107 patients enrolled: in 21% from chemohormonal (CHT) to hormonal therapy (HT) and in 11% from HT to CHT. RS was associated with the likelihood of change from HT to CHT (P < 0.001) and from CHT to HT (P < 0.001). Confidence of oncologists in treatment recommendations increased for 60% of cases. Higher tumor grade (P = 0.007) and a high proliferative index (Ki-67) (P = 0.023) were significantly associated with a greater chance of changing from HT to CHT, while positive progesterone receptor status (P = 0.002) with a greater probability of changing from CHT to HT. CONCLUSIONS: Results from the first prospective European study are consistent with published experience and use of the RS as proposed in European clinical practice guidelines and provide evidence on how Oncotype DX and clinicopathological factors are complementary and patient selection may be improved.

Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer.

BACKGROUND: Poly(ADP-ribose)polymerase-1 (PARP-1) is a highly promising novel target in breast cancer. However, the expression of PARP-1 protein in breast cancer and its associations with outcome are yet poorly characterized. PATIENTS AND METHODS: Quantitative expression of PARP-1 protein was assayed by a specific immunohistochemical signal intensity scanning assay in a range of normal to malignant breast lesions, including a series of patients (N = 330) with operable breast cancer to correlate with clinicopathological factors and long-term outcome. RESULTS: PARP-1 was overexpressed in about a third of ductal carcinoma in situ and infiltrating breast carcinomas. PARP-1 protein overexpression was associated to higher tumor grade (P = 0.01), estrogen-negative tumors (P < 0.001) and triple-negative phenotype (P < 0.001). The hazard ratio (HR) for death in patients with PARP-1 overexpressing tumors was 7.24 (95% CI; 3.56-14.75). In a multivariate analysis, PARP-1 overexpression was an independent prognostic factor for both disease-free (HR 10.05; 95% CI 5.42-10.66) and overall survival (HR 1.82; 95% CI 1.32-2.52). CONCLUSIONS: Nuclear PARP-1 is overexpressed during the malignant transformation of the breast, particularly in triple-negative tumors, and independently predicts poor prognosis in operable invasive breast cancer.

Pharmacodynamics: biological activity of targeted therapies in clinical trials.

Anticancer drug discovery and development in cancer are currently undergoing of fast transformation. The selection of a therapeutic and effective dose using conventional cytotoxic agents has been based on the consecution of the maximally tolerated dose. However, this principle does not apply for new targeted therapies, where the definition of the optimal biologic dose (OBD) should be preferred. The definition of OBD might be established based on pharmacokinetic endpoints and, ideally, on pharmacodynamic assays by demonstrating directly the biological effect on the target and its downstream molecules in normal or tumor tissues. Normal tissues, such as peripheral blood mononuclear cells, skin or mucosa, may be excellent surrogates for explore the exposure of a drug and the dynamic target inhibition in vivo. In addition, tumor pharmacodynamic assays may determine the biologic effects of a therapy because tumor cells respond in a different way to targeted drugs than normal tissues, and to identify biomarkers that would permit to predict the individual response. In conclusion, these studies provide demonstration of proof of concept for biological and molecular mechanisms of selected drug, to select the appropriate population to be treated, to help the interpretation of clinical data, to inform the identification of optimal dose and schedule, to evaluate the clinical response and to contribute to take decisions for final approval by authorities.

Activation of nuclear factor-kappa B is linked to resistance to neoadjuvant chemotherapy in breast cancer patients.

The nuclear factor (NF)-kappaB system is a promising anticancer target due to its role in oncogenesis and chemoresistance in preclinical models. To provide evidence in a clinical setting on the role of NF-kappaB in breast cancer, we aimed to study the value of basal NF-kappaB/p65 in predicting resistance to neoadjuvant chemotherapy, and to characterise the pharmacodynamic changes in NF-kappaB/p65 expression following chemotherapy in patients with locally advanced breast cancer. Pre- and post-chemotherapy tumour specimens from 51 breast cancer patients treated with anthracycline- and/or taxane-containing neoadjuvant chemotherapy were assayed by immunohistochemistry for NF-kappaB/p65 subcellular expression. We studied NF-kappaB/p65, a well-characterised member of the NF-kappaB family that undergoes nuclear translocation when NF-kappaB is activated. Activation of NF-kappaB (i.e. nuclear NF-kappaB/p65 staining in pre-therapy specimens) was linked to chemoresistance. Patients with NF-kappaB/p65 nuclear staining in pre-treatment samples had a 20% clinical response rate, while patients with undetected nuclear staining had a 91% response rate to chemotherapy (P = 0.002). Notably, four patients achieved a complete histological response and none of them had pre-treatment NF-kappaB/p65 nuclear staining. Moreover, the number of patients with NF-kappaB/p65 activation increased after chemotherapy exposure. It is concluded that NF-kappaB/p65 activation assayed by immunohistochemistry is a predictive factor of resistance to neoadjuvant chemotherapy in breast cancer patients. Moreover, NF-kappaB activation was inducible following chemotherapy in a proportion of breast cancer patients. These novel clinical findings strengthen the rationale for the use of NF-kappaB inhibitors to prevent or overcome chemoresistance in breast cancer.

Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer. PANK-ras I Project Investigators.

PURPOSE: To assess the prevalence and prognostic significance of Ki-ras codon 12 mutations in extrahepatic biliary system cancer (EBSC). PATIENTS AND METHODS: Patients diagnosed with EBSC between 1980 and 1990 (N = 111) were selected from two hospitals. DNA was amplified from paraffin-embedded tissues and mutations in codon 12 of Ki-ras were detected using the artificial restriction fragment-length polymorphism (RFLP) technique. RESULTS: Tissue was available from 68.5% of patients. The prevalence of mutations was 41%. There was no association between mutations and clinical and pathologic characteristics; however, mutations in Ki-ras were associated with survival, with a median survival duration of 7.7 months for patients with wild-type Ki-ras and 1.7 months for patients with mutated tumors (hazards ratio [HR] = 1.67; P = .075). Among patients with stage I to II tumors, the chance of dying of patients with the mutation was 7.8 times higher than that of patients without the mutation (P = .087); the corresponding HR for patients with stage III to IV disease was 2.9 (P = .003). After adjusting for age, tumor site, histology, differentiation, and stage, the HR for Ki-ras mutations was 2.12 (P = .026). CONCLUSION: Ki-ras codon 12 mutations are an independent prognostic indicator in patients with EBSC. Mutation detection may be of help in the management of these patients.

Reactive vascular lesion of nasal septum simulating angiosarcoma in a cocaine abuser.

We report the case of an exuberant ulcerative angiomatoid nasal lesion in a cocaine abuser. The lesion was made up of polymorphous endothelial cells with occasional mitoses, arranged in a lobular pattern with infiltrative-looking areas. There were extensive areas of thrombosis with focal recanalization. Intravascular proliferation was not observed. The clinical, radiological, and histological features suggested hemangiosarcoma as the main differential diagnosis, but the lobular architecture of the lesion and the widespread thrombosis favoured the diagnosis of a benign reactive process.

Structure of the latissimus dorsi muscle and respiratory function.

The aim of this study was to evaluate whether respiratory function influences the structure of the latissimus dorsi muscle (LD). Twelve patients (58 +/- 10 yr) undergoing thoracotomy were studied. Lung and respiratory muscle function were evaluated before surgery. Patients showed a forced expired volume in 1 s (FEV1) of 67 +/- 16% of the reference value, an FEV1-forced vital capacity ratio of 69 +/- 9%, a maximal inspiratory pressure of 101 +/- 21% of the reference value, and a tension-time index of the diaphragm (TTdi) of 0.04 +/- 0.02. When patients were exposed to 8% CO2 breathing, TTdi increased to 0.06 +/- 0.03 (P < 0.05). The structural analysis of LD showed that 51 +/- 5% of the fibers were type I. The diameter was 56 +/- 9 microns for type I fibers and 61 +/- 9 microns for type II fibers, whereas the hypertrophy factor was 87 +/- 94 and 172 +/- 208 for type I and II fibers, respectively. Interestingly, the histogram distribution of the LD fibers was unimodal in two of the three individuals with normal lung function and bimodal (additional mode of hypertrophic fibers) in seven of the nine patients with chronic obstructive pulmonary disease. An inverse relationship was found between the %FEV1-forced vital capacity ratio and both the diameter of the fibers (type I: r = -0.773, P < 0.005; type II: r = -0.590, P < 0.05) and the hypertrophy factors (type I: r = -0.647, P < 0.05; type II: r = -0.575, P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Association between coffee drinking and K-ras mutations in exocrine pancreatic cancer. PANKRAS II Study Group.

STUDY OBJECTIVE: To analyse the relation between coffee consumption and mutations in the K-ras gene in exocrine pancreatic cancer. DESIGN: Case-case study. Consumption of coffee among cases with the activating mutation in the K-ras gene was compared with that of cases without the mutation. SETTING AND PATIENTS: All cases of pancreatic cancer newly diagnosed at five hospitals in Spain during three years were included in the PANKRAS II Study (n = 185, of whom 121 whose tissue was available for molecular analysis are the object of the present report). Over 88% were personally interviewed in hospital. DNA was amplified from paraffin wax embedded tissues, and mutations in codon 12 of K-ras were detected by the artificial RFLP technique. MAIN RESULTS: Mutations were found in tumours from 94 of 121 patients (77.7%). Mutations were more common among regular coffee drinkers than among non-regular coffee drinkers (82.0% v 55.6%, p = 0.018, n = 107). The odds ratio adjusted by age, sex, smoking and alcohol drinking was 5.41 (95% CI 1.64, 17.78). The weekly intake of coffee was significantly higher among patients with a mutated tumour (mean of 14.5 cups/week v 8.8 among patients with a wild type tumour, p < 0.05). With respect to non-regular coffee drinkers, the odds ratio of a mutated tumour adjusted by age, sex, smoking and alcohol drinking was 3.26 for drinkers of 2-7 cups/week, 5.77 for drinkers of 8-14 cups/week and 9.99 for drinkers of > or = 15 cups/week (p < 0.01, test for trend). CONCLUSIONS: Pancreatic cancer cases without activating mutations in the K-ras gene had drank significantly less coffee than cases with a mutation, with a significant dose response relation: the less they drank, the less likely their tumours were to harbour a mutation. In exocrine pancreatic cancer the K-ras gene may be activated less often among non-regular coffee drinkers than among regular drinkers. Caffeine, other coffee compounds or other factors with which coffee drinking is associated may modulate K-ras activation.

[Immunohistochemical study of inflammatory infiltrates in minor salivary glands in Sjögren's syndrome and other autoimmune diseases]. / Estudio inmunohistoquímico del infiltrado inflamatorio de la glándula salival menor en el síndrome de Sjögren y otras enfermedades autoinmunes.

BACKGROUND: A study of the phenotype, activation and adhesive cells factors and cytokines in minor salivary glands in patients with primary Sjögren's syndrome (pSS), secondary Sjögren's syndrome (sSS) and autoimmune diseases (AD) without Sjögren's syndrome. PATIENTS AND METHODS: We have studied the minor salivary glands in 30 patients with pSS, 30 patients with sSS, 19 patients with AD without SS and 18 controls, using immunohistochemical techniques to analyze the molecular expression of CD3, CD4, CD8, CD20, CD25, CD14, CD56, CD11a, CDw50 (ICAM-3), HLA-DR, IL-1, TNF-alpha and IFN-gamma in lymphocytic infiltration and epithelial cells. RESULTS: Phenotype features were similar in patients with pSS and sSS, except that CD20+ lymphocyte expression was significantly higher in the sSS group (p = 0.023). The patients affected by AD without SS had activated lymphocytes in minor salivary glands in a similar manner to patients affected by pSS and sSS. No significant differences were found in HLA-DR expression in epithelial cells. We found unusual CD25 expression in epithelial cells in patients with SS but not in patients with AD without SS. The differences between pSS and sSS are related to SS theoretical time development and to immunosuppressive treatments. CONCLUSIONS: The immunohistochemical pattern of minor salivary glands is similar in patients with pSS and sSS. Patients with AD are likely to develop immunological changes in minor salivary glands attributable to activated lymphocytes.

[Acquired immunodeficiency syndrome and T-cell non-Hodgkin's lymphoma]. / Síndrome de inmunodeficiencia adquirida y linfoma no hodgkiniano de células T.

The clinical observation of a 40 years old male presenting acquired immune deficiency syndrome and T-cell non Hodgkin's lymphoma is presented. The patient was treated with COMET-A regimen (cyclophosphamide, vincristine, methotrexate, etoposide and cytarabine) and a complete remission was obtained.